Dual Trade of Bcl-2 and Bcl-xL in Islet Physiology

Apoptosis is now recognized as a predominant mechanism by which b cells are destroyed in both type 1 and type 2 diabetes (1). Proand antiapoptotic members of the Bcl-2 family are central regulators involved in b-cell fate decision between life and death in response to physiological insults. The intricate interplay and balance between members of this family regulate apoptosis by controlling mitochondrial cell death signaling, the so-called intrinsic pathway (2). The Bcl-2 family is divided into three subgroups as follows: 1) the antiapoptotic Bcl-2–like proteins (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, and A1/Bfl1) that possess four independent and highly conserved Bcl-2 homology (BH) domains (BH-1 to -4); 2) the proapoptotic Bax-like proteins (Bax, Bak, and Bok/Mtd), which also harbor the four BH domains; and 3) proapoptotic members typified by a single BH-3 domain (Bid, Bim/Bod, Bad, Bmf, Bik/Nbk, Blk, NoxA, Puma/Bbc3, and Hrk/DP5). Members of this last subgroup initiate the apoptotic-signaling cascade by interacting with antiapoptotic members (3). In addition, intracellular calcium activity ([Ca]i) is an important second messenger that initiates the apoptotic program (4) as well as being essential in metabolism secretion coupling that drives the Ca sensor of the exocytotic machinery (5). Given the importance of Bcl-2 and Bcl-xL as prosurvival sentinels of the mitochondria, combined with the indispensable function of this organelle in b-cell metabolism secretion coupling, these proteins have been the targets of numerous studies in which expression levels were manipulated with the goal of improving islet viability. The study by Zhou et al. (6) in 2000 was the first to provide proof of concept that overexpression of Bcl-xL in b cells blunted stressed-induced apoptosis. Unexpectedly, one of the transgenic lines expressing high levels of Bcl-xL also displayed severe hyperglycemia. Glucose intolerance in these animals was linked to impaired nutrient-induced insulin secretion caused by alterations in mitochondrial ATP generation and intracellular Ca handling (6). Substantiating this study, Pax4-induced Bcl-xL expression in rat islets also resulted in curtailed b-cell metabolism-secretion coupling through blunted mitochondrial Ca concentrations and decreased ATP production (7). These early studies cautioned that Bcl2 protein family members might not only be involved in regulating apoptosis but also be implicated in a day-to-day control of cellular function. Consistent with this premise was the elegant finding by Danial et al. (8) that Bad forms a complex with glucokinase in order to regulate glucosedriven mitochondrial metabolism and insulin secretion in islets. Nonetheless, other studies have tended to argue against the role of these proteins in glucose metabolism. Indeed, transgenic mice either overexpressing Bcl-2 or bearing a deletion in the BCLXL gene specifically in b cells were not reported to display any aberrant alterations in glucose metabolism (9,10). Thus, the relative contributions of antiapoptotic versus alternative functions of Bcl-2 and Bcl-xL for overall b-cell survival and performance remain controversial. In this issue of Diabetes, Luciani et al. (11) address this controversy and convincingly demonstrate that Bcl-2 or Bcl-xL dampens glucose-induced insulin secretion and highlight the role of these prosurvival proteins as critical physiological integrators balancing life and death with metabolism secretion coupling in the b cell. In a first approach to authenticate this dual functionality, the authors used the small-molecule antagonist compound 6 (C6) and YC137 to pharmacologically hinder Bcl-2 and Bcl-xL. These antagonists bind to and displace proapoptotic members such as Bad from Bcl-2 and Bcl-xL, ultimately inducing apoptosis. In these experiments, C6 caused a rapid disruption of the Bcl-xL/Bad complex as well as a redistribution of Bax from the cytosol to mitochondria resulting in the release of cytochrome c, activation of caspase-3, and b-cell death. As antagonist-induced apoptosis was usually detected 2 h posttreatment, the authors argued that cellular events occurring within this time frame were likely independent of the central apoptotic events. In this context, the most impressive physiological event occurring subsequent to antagonistic treatment was the rapid triggering of [Ca]i in cells that mimicked the effect of glucose signaling. Yet, cells were cultured in the presence of low glucose, suggesting increased performance of mitochondrial metabolism leading to Ca influx and potentially insulin secretion. Luciani et al. (11) methodically dissect the pathway leading to glucose-induced insulin secretion using various inhibitors and demonstrate that antagonizing Bcl-2/ Bcl-xL in islets recapitulates cellular events associated with metabolism secretion coupling in b-cells: increased ATP production causing closure of the ATP-sensitive K channel with the subsequent depolarization of the plasma membrane and opening of the L-type Ca channel resulting in submembranous increase in [Ca]i and ultimately insulin exocytosis. Low glucose levels as well as a sustained From the Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain; and the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain. Corresponding author: Benoit R. Gauthier, [email protected]. DOI: 10.2337/db12-1023 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 170.